An ortho-directed C–H borylation/Suzuki coupling sequence in the formation of biphenylbenzylic amines

Abstract

A C–H borylation/Suzuki–Miyaura coupling sequence is reported using benzylic amines to direct the C–H borylation to the ortho C–H bond. Both aryl bromides and iodides were coupled to the resulting arylboronate esters. A series of biphenylbenzylic amines are reported, requiring a single purification in the two-step reaction sequence.

---

Metal-catalysed C–H borylation reactions have received significant attention over the past 15 years,^1–3 advancing early stoichiometric reactions of metal boryl complexes with a C–H bond of the solvent^4–6 to catalytic methods that require 1–2 equivalents of the substrate. Early stoichiometric and catalytic reactions provided sterically-controlled selectivity, resulting in functionalization of primary over secondary C–H bonds for alkanes and selectivity for the meta or para position over the ortho position with arenes.^2,7,8 Since 2008, several approaches to substrate-directed C–H borylation have resulted in a number of methods that provide ortho-selective C–H borylation of arenes.^9,10 The extent of functional groups that can now be used to direct arene C–H borylation includes silanes,^9,11 halides,¹² esters,^12–15 amides,^12,14 carbamates,^16,17 ethers,^12,14 amines,^18–20 imines,^21–23 and phosphines.²⁴ The ability to utilize nitrogen directing groups in C–H borylation is of particular interest to the synthetic community due to the prevalence of nitrogen in biologically relevant targets.

The synthetic utility of metal-catalysed C–H borylation reactions lies in the versatility of the C–B bond, which is readily converted into C–O, C–N, and C–C bonds.^25–31 Many examples of C–H borylation reactions in target-directed syntheses have now appeared in the literature,³ demonstrating the power of converting an otherwise unreactive C–H bond into a variety of C–Y bonds. Although transformations involving C–B bonds are generally robust and functional group tolerant, the presence of an adjacent directing group can cause significant complications in the formation of new C–Y bonds. These limitations are particularly apparent with Lewis base directing groups that can significantly alter the reactivity of a metal-catalysed transformation utilizing a C–B bond. With this limitation in mind, the Suzuki–Miyaura coupling of arylboronates^27,32–34 derived from the iridium-catalysed C–H borylation of benzylic amines is reported herein. This transformation utilizes our recently reported amine-directed C–H borylation of benzylic amines using readily available hemi-labile diamine ligands,^19,35 ultimately providing biphenylbenzylic amines upon subjecting the resulting arylboronate esters to Suzuki–Miyaura coupling conditions.^36–39 Biphenylbenzylic amines are prevalent in a number of biologically active compounds, including anacetrapib (cholesterol ester transfer protein inhibitor in phase III clinical trials)⁴⁰ and allocolchicine⁴¹ (binds to tubulin and disrupts tubulin polymerization) (Fig. 1).

Fig. 1 Structures of anacetrapib and allocolchicine with the biphenylbenzylic amine highlighted in red.

Access to the desired biphenylbenzylic amines was initiated by combining the amine-directed C–H borylation to Suzuki–Miyaura reaction conditions that are known for related boronic acids with an ortho-situated benzylic amine.⁴² 2-Fluoro-N,N-dimethylbenzylamine was used initially since only one ortho C–H bond is available for functionalization. C–H borylation of 2-fluoro-N,N-dimethylbenzylamine was accomplished with 1.5 mol% [Ir(μ-OMe)(COD)]₂, 3 mol% picolylamine (picNH₂) and 0.83 equivalent of B₂pin₂ (a small excess of benzylic amine improves selectivity for the mono-ortho borylation product).¹⁹ Addition of iodobenzene to the unpurified C–H borylation product in the presence of a catalytic amount of Pd(PPh₃)₄ and aqueous sodium hydroxide provided the desired biphenylbenzylic amine 1 in 68% yield over the two-step reaction sequence (Scheme 1, Table 1).⁴³ Encouraged by this result, additional benzylic amines were subjected to these reaction conditions and coupled to aryl halides. Additional 2-substituted benzylic amines were effective in the reaction sequence, providing 2 and 3 in good yield. Aryl bromides were shown to react under identical conditions to provide 2 and 4. Borylation and coupling at the sterically encumbered C–H bond of the mesitylene-derived benzylic amine provided 5 in good yield. A substituent in the benzylic position was also tolerated under the reaction conditions, providing 6 in high yield.

Scheme 1 C–H borylation/Suzuki–Miyaura coupling sequence.

Table 1 Scope of biphenylbenzylic amines accessed through C–H borylation/Suzuki coupling sequence (Scheme 1)^a

R	ArX	Product	Yield
a 0.83 equivalent of B2pin2 to benzylamine in C–H borylation; 1.1 equivalents of ArX to arene used in Suzuki coupling. Yield based on stoichiometry of the benzylamine substrate used in C–H borylation.
2-F	C6H5I		68%
2-F	4-MeC6H4Br		52%
2-Me	4-CF3C6H4I		59%
4-Me	4-MeOC6H4Br		55%
1′-Me	3-CF3C6H4I		57%
3,5-Me2	C6H5I		79%

---

Unsymmetrical 3-substituted benzylic amines were investigated next to access highly-substituted biphenylbenzylic amines (Scheme 2). These benzylic amines are challenging substrates in the C–H borylation reaction due to the possibility of 3 different ortho borylation products (borylation at the 6-position-major, borylation at the 2-position, and bis-ortho borylation). We recently reported a study on the role of the ligand in C–H borylation and found that 2-(N-benzylamino)pyridine (pyNHBn) provides improved yields and selectivity over picolylamine for these substrates.³⁵ The C–H borylation/Suzuki coupling sequence was examined using pyNHBn in place of picolylamine, providing high yields of the desired biphenylbenzylic amines (Scheme 2, Table 2). Electron-withdrawing aryl bromides provided significantly higher yield (7) than the corresponding electron-rich aryl bromide (8). The 3-methoxy-substituted benzylic amine was shown to undergo both transformations, providing 9 in high yield. Notably, the presence of the 3-chloro substituent was tolerated during both metal-catalysed reactions in spite of the propensity of C–Cl bonds to undergo oxidative addition, providing 10 in 62% yield. The presence of this reactive C–Cl bond in 10 provides an additional synthetic handle for further transformations in target-directed synthesis.

Scheme 2 C–H borylation/Suzuki coupling with 3-substituted benzylic amines.

Table 2 C–H borylation/Suzuki coupling sequence with 3-substituted benzylic amines (Scheme 2)^a

R	ArX	Product	Yield
a 0.83 equivalent of B2pin2 to benzylamine in C–H borylation; 1.1 equivalents of ArX to arene used in Suzuki coupling. Yield based on stoichiometry of the benzylamine substrate used in C–H borylation.
3-Me	3-MeCOC6H4Br		84%
3-Me	4-MeOC6H4Br		40%
3-OMe	4-EtCOC6H4Br		79%
3-Cl	3-CF3C6H4I		62%

---

Conclusions

Efficient synthesis of biphenylbenzylic amines, a common core structure in biologically active compounds, has been reported. The iridium-catalysed C–H borylation provides reactive arylboronate esters that were subjected to Suzuki–Miyaura coupling conditions without purification of the arylboronate ester intermediates. A wide range of functional groups are tolerated under the reaction conditions, providing highly-functionalized biphenylbenzylic amines.

Experimental section

General methods

All procedures involving air- or moisture-sensitive reagents were performed in oven-dried glassware under purified nitrogen, either in an inert atmosphere glovebox or by standard Schlenk techniques. All solvents were dried and degassed by standard procedures unless employed for reaction work-up or purification. TLC analysis was performed on 60 Å silica layer fluorescence UV plates. Flash column chromatography was carried out on hand-packed columns of 70–230 mesh silica gel, 40–63 microns. NMR spectra were collected on a Unity Inova spectrometer at 500 MHz for ¹H NMR, 125 MHz for ¹³C NMR or on a Mercury spectrometer at 100 MHz for ¹³C NMR. ¹H NMR spectra are referenced to CDCl₃ at 7.26 ppm, or to an internal tetramethylsilane (TMS) standard at 0.00 ppm. The ¹H NMR spectral data are reported as follows: chemical shift ppm, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, hex = hextet, sep = septet, oct = octet, m = multiplet), coupling constants (Hz), and integration. ¹³C NMR spectra are referenced to CDCl₃ at 77.0 ppm. Attenuated total reflection IR (ATR-IR) spectra were obtained with a Jasco FT-IR-480 Plus and absorptions were reported in cm⁻¹.

Chloroform-d, bis(pinacolato)diboron, [Ir(μ-OMe)(COD)]₂, 2-(aminomethyl)pyridine, 2-(N-benzylamino)pyridine, Pd(PPh₃)₄, and all required benzylbromides and aryl halides were purchased and used without purification. All benzylamines were known and synthesized by the same procedure.¹⁹

General procedure for the C–H borylation³⁵/Suzuki–Miyaura coupling of benzylic amines⁴²

To a 50 mL PTFE-valved reaction tube, equipped with a stir bar and charged with [Ir(μ-OMe)(COD)]₂ (0.020 g, 0.030 mmol), was added 2-(aminomethyl)pyridine (0.0062 mL, 0.060 mmol) or 2-(N-benzylamino)pyridine (0.011 g, 0.060 mmol), B₂pin₂ (0.423 g, 1.67 mmol), benzylamine (2.00 mmol), and 4.0 mL of methylcyclohexane. After 16 h at 70 °C, the volatiles were removed in vacuo.

To a round bottom flask charged with Pd(PPh₃)₄ (0.046 g, 0.040 mmol) was added aryl halide (2.20 mmol) and toluene (10 mL). After 20 minutes at 22 °C the crude ortho-borylated N,N-dimethylbenzylamine (2.00 mmol) and aqueous sodium hydroxide (5.0 M, 2.00 mL, 10 mmol) were added and the round bottom flask was fitted with a reflux condenser and flushed with N₂ gas. After 4–20 h at 100 °C, the reaction mixture was diluted with diethyl ether (50 mL), filtered through a pad of Celite with additional diethyl ether (200 mL) and concentrated in vacuo. Purification by silica gel flash column chromatography provided the biphenylbenzylic amine.

Acknowledgements

Financial support from the National Science Foundation (CHE-1151092), the University of San Diego, Research Corporation for Science Advancement, and the National Science Foundation for NMR (0417731) facilities at USD. Dr John Greaves (University of California, Irvine) for mass spectrometry.

Notes and references

1. I. A. I. Mkhalid, J. H. Barnard, T. B. Marder, J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890–931.
2. J. F. Hartwig, Chem. Soc. Rev., 2011, 40, 1992–2002.
3. J. F. Hartwig, Acc. Chem. Res., 2012, 45, 864–873.
4. K. M. Waltz, X. He, C. Muhoro and J. F. Hartwig, J. Am. Chem. Soc., 1995, 117, 11357–11358.
5. C. N. Iverson and M. R. Smith III, J. Am. Chem. Soc., 1999, 121, 7696–7697.
6. S. Shimada, A. S. Batsanov, J. A. K. Howard and T. B. Marder, Angew. Chem., Int. Ed., 2001, 40, 2168–2171.
7. C. S. Wei, C. A. Jiménez-Hoyos, M. F. Videa, J. F. Hartwig and M. B. Hall, J. Am. Chem. Soc., 2010, 132, 3078–3091.
8. H. Tajuddin, P. Harrisson, B. Bitterlich, J. C. Collings, N. Sim, A. S. Batsanov, M. S. Cheung, S. Kawamorita, A. C. Maxwell, L. Shukla, J. Morris, Z. Lin, T. B. Marder and P. G. Steel, Chem. Sci., 2012, 3, 3505–3515.
9. T. A. Boebel and J. F. Hartwig, J. Am. Chem. Soc., 2008, 130, 7534–7535.
10. A. Ros, R. Fernández and J. M. Lassaletta, Chem. Soc. Rev., 2014, 43, 3229–3243.
11. D. W. Robbins, T. A. Boebel and J. F. Hartwig, J. Am. Chem. Soc., 2010, 132, 4068–4069.
12. S. Kawamorita, H. Ohmiya, K. Hara, A. Fukuoka and M. Sawamura, J. Am. Chem. Soc., 2009, 131, 5058–5059.
13. T. Ishiyama, H. Isou, T. Kikuchi and N. Miyaura, Chem. Commun., 2010, 46, 159–161.
14. B. Ghaffari, S. M. Preshlock, D. L. Plattner, R. J. Staples, P. E. Maligres, S. W. Krska, R. E. Maleczka Jr. and M. R. Smith III, J. Am. Chem. Soc., 2014, 136, 14345–14348.
15. S. Kawamorita, H. Ohmiya and M. Sawamura, J. Org. Chem., 2010, 75, 3855–3858.
16. P. C. Roosen, V. A. Kallepalli, B. Chattopadhyay, D. A. Singleton, R. E. Maleczka Jr. and M. R. Smith III, J. Am. Chem. Soc., 2012, 134, 11350–11353.
17. K. Yamazaki, S. Kawamorita, H. Ohmiya and M. Sawamura, Org. Lett., 2010, 12, 3978–3981.
18. S. Kawamorita, T. Miyazaki, H. Ohmiya, T. Iwai and M. Sawamura, J. Am. Chem. Soc., 2011, 133, 19310–19313.
19. A. J. Roering, L. V. A. Hale, P. A. Squier, M. A. Ringgold, E. R. Wiederspan and T. B. Clark, Org. Lett., 2012, 14, 3558–3561.
20. S. Konishi, S. Kawamorita, T. Iwai, P. G. Steel, T. B. Marder and M. Sawamura, Chem. – Asian J., 2014, 9, 434–438.
21. A. Ros, B. Estepa, R. López-Rodríguez, E. Álvarez, R. Fernández and J. M. Lassaletta, Angew. Chem., Int. Ed., 2011, 50, 11724–11728.
22. A. Ros, R. López-Rodríguez, B. Estepa, E. Álvarez, R. Fernández and J. M. Lassaletta, J. Am. Chem. Soc., 2012, 134, 4573–4576.
23. I. Sasaki, T. Amou, H. Ito and T. Ishiyama, Org. Biomol. Chem., 2014, 12, 2041–2044.
24. K. M. Crawford, T. R. Ramseyer, C. J. A. Daley and T. B. Clark, Angew. Chem., Int. Ed., 2014, 53, 7589–7593.
25. H. C. Brown, G. W. Kramer, A. B. Levy and M. M. Midland, Organic Syntheses via Boranes, Wiley-Interscience, New York, 1975.
26. H. C. Brown and M. Zaidlewicz, Organic Syntheses via Boranes-Recent Developments, Aldrich Chemical Company, Milwaukee, 2001.
27. N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483.
28. D. S. Matteson, Tetrahedron, 1998, 54, 10555–10607.
29. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, ed. D. G. Hall, Wiley-VCH, Weinheim, 2nd edn, vol. 1, 2011.
30. Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, ed. D. G. Hall, Wiley-VCH, Weinheim, 2nd edn, vol. 2, 2011.
31. D. Leonori and V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174–3183.
32. A. Suzuki, J. Organomet. Chem., 1999, 576, 147–168.
33. G. A. Molander and B. Canturk, Angew. Chem., Int. Ed., 2009, 48, 9240–9261.
34. G. C. Fu, Acc. Chem. Res., 2008, 41, 1555–1564.
35. L. V. A. Hale, K. A. McGarry, M. A. Ringgold and T. B. Clark, Organometallics, 2015, 34, 51–55.
36. G. A. Chotana, V. A. Kallepalli, R. E. Maleczka Jr. and M. R. Smith III, Tetrahedron, 2008, 64, 6103–6114.
37. D. W. Robbins and J. F. Hartwig, Org. Lett., 2012, 14, 4266–4269.
38. I. Ahmed and D. A. Clark, Org. Lett., 2014, 16, 4332–4335.
39. P. Harrisson, J. Morris, P. G. Steel and T. B. Marder, Synlett, 2009, 147–150.
40. A. M. J. Gotto, U. Kher, M. S. Chatterjee, Y. Liu, X. S. Li, S. Vaidya, C. P. Cannon, E. A. Brinton, J. E. Moon, S. Shah, H. M. Dansky, Y. Mitchel and P. Barter, J. Cardiovasc. Pharmacol. Ther., 2014, 19, 543–549.
41. B. Pérez-Ramírez, M. J. Gorbunoff and S. N. Timasheff, Biochemistry, 1998, 37, 1646–1661.
42. P.-L. Boudreault, S. Cardinal and N. Voyer, Synlett, 2010, 2449–2452.
43. Attempts to conduct the Suzuki–Miyaura coupling reaction without switching solvents resulted in decreased reaction yields. For examples of a C–H borylation/Suzuki–Miyaura coupling sequence without changing the solvent, see ref. 38 and 39.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data, and ¹H and ¹³C NMR spectra for compounds 1–10. See DOI: 10.1039/c4qo00348a

---